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Literature DB >> 7724556

Protein structure-based design of potent orally bioavailable, nonpeptide inhibitors of human immunodeficiency virus protease.

S H Reich¹, M Melnick, J F Davies, K Appelt, K K Lewis, M A Fuhry, M Pino, A J Trippe, D Nguyen, H Dawson.

Abstract

A class of potent nonpeptidic inhibitors of human immunodeficiency virus protease has been designed by using the three-dimensional structure of the enzyme as a guide. By employing iterative protein cocrystal structure analysis, design, and synthesis the binding affinity of the lead compound was incrementally improved by over four orders of magnitude. An inversion in inhibitor binding mode was observed crystallographically, providing information critical for subsequent design and highlighting the utility of structural feedback in inhibitor optimization. These inhibitors are selective for the viral protease enzyme, possess good antiviral activity, and are orally available in three species.

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Year: 1995 PMID： 7724556 PMCID： PMC42153 DOI： 10.1073/pnas.92.8.3298

Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205

15 in total

1. Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostere.

Authors: A Krohn; S Redshaw; J C Ritchie; B J Graves; M H Hatada
Journal: J Med Chem Date: 1991-11 Impact factor: 7.446

2. Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere.

Authors: D P Getman; G A DeCrescenzo; R M Heintz; K L Reed; J J Talley; M L Bryant; M Clare; K A Houseman; J J Marr; R A Mueller
Journal: J Med Chem Date: 1993-01-22 Impact factor: 7.446

3. De novo design of enzyme inhibitors by Monte Carlo ligand generation.

Authors: D K Gehlhaar; K E Moerder; D Zichi; C J Sherman; R C Ogden; S T Freer
Journal: J Med Chem Date: 1995-02-03 Impact factor: 7.446

4. Structure-based design of HIV protease inhibitors: 4-hydroxycoumarins and 4-hydroxy-2-pyrones as non-peptidic inhibitors.

Authors: S Thaisrivongs; P K Tomich; K D Watenpaugh; K T Chong; W J Howe; C P Yang; J W Strohbach; S R Turner; J P McGrath; M J Bohanon
Journal: J Med Chem Date: 1994-09-30 Impact factor: 7.446

5. Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors.

Authors: J F Morrison
Journal: Biochim Biophys Acta Date: 1969

6. Rational design of peptide-based HIV proteinase inhibitors.

Authors: N A Roberts; J A Martin; D Kinchington; A V Broadhurst; J C Craig; I B Duncan; S A Galpin; B K Handa; J Kay; A Kröhn
Journal: Science Date: 1990-04-20 Impact factor: 47.728

7. High-level expression of self-processed HIV-1 protease in Escherichia coli using a synthetic gene.

Authors: Z Hostomsky; K Appelt; R C Ogden
Journal: Biochem Biophys Res Commun Date: 1989-06-30 Impact factor: 3.575

8. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor.

Authors: J P Vacca; B D Dorsey; W A Schleif; R B Levin; S L McDaniel; P L Darke; J Zugay; J C Quintero; O M Blahy; E Roth
Journal: Proc Natl Acad Sci U S A Date: 1994-04-26 Impact factor: 11.205

9. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors.

Authors: P Y Lam; P K Jadhav; C J Eyermann; C N Hodge; Y Ru; L T Bacheler; J L Meek; M J Otto; M M Rayner; Y N Wong
Journal: Science Date: 1994-01-21 Impact factor: 47.728

10. Symmetry-based inhibitors of HIV protease. Structure-activity studies of acylated 2,4-diamino-1,5-diphenyl-3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol.

Authors: D J Kempf; L Codacovi; X C Wang; W E Kohlbrenner; N E Wideburg; A Saldivar; S Vasavanonda; K C Marsh; P Bryant; H L Sham
Journal: J Med Chem Date: 1993-02-05 Impact factor: 7.446

7 in total

Protein structure-based design of potent orally bioavailable, nonpeptide inhibitors of human immunodeficiency virus protease.

1. Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostere.

2. Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere.

3. De novo design of enzyme inhibitors by Monte Carlo ligand generation.

4. Structure-based design of HIV protease inhibitors: 4-hydroxycoumarins and 4-hydroxy-2-pyrones as non-peptidic inhibitors.

5. Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors.

6. Rational design of peptide-based HIV proteinase inhibitors.

7. High-level expression of self-processed HIV-1 protease in Escherichia coli using a synthetic gene.

8. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor.

9. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors.

10. Symmetry-based inhibitors of HIV protease. Structure-activity studies of acylated 2,4-diamino-1,5-diphenyl-3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol.

1. Designing the molecular future.

2. Perspective: Alchemical free energy calculations for drug discovery.

Review 3. Using bacterial genomes and essential genes for the development of new antibiotics.

4. Beyond picomolar affinities: quantitative aspects of noncovalent and covalent binding of drugs to proteins.

Review 5. Binding of small-molecule ligands to proteins: "what you see" is not always "what you get".

Review 6. In silico discovery of aminoacyl-tRNA synthetase inhibitors.

7. Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity.